Parkinson's disease is the second most common neurodegenerative disease in the US and it has no cure. Thanks to rapid advances in genetics, important molecular targets in the pathogenesis of Parkinson's disease have been identified. Mutations in the Leucine rich repeat kinase 2 (Lrrk2) are associated with an autosomal dominant form of Parkinson's. An understanding of the molecular regulation and cellular signaling pathways of Lrrk2 in dopaminergic neurons is a necessary in first step in determining whether Lrrk2 or its signaling partners might be exploited as therapeutic targets in the treatment of both familial and idiopathic Parkinson's disease. We plan to use cell biological, biochemical, and mass spectrometric techniques, complemented by molecular modeling, to: 1.) determine the mechanistic nature of the Lrrk2 kinase domain mutations found in Parkinson's disease; 2.) investigate the molecular mechanisms by which Lrrk2 kinase activity is regulated; and 3) Identify components of Lrrk2 signaling complexes. The proposed research will provide much needed insight into the critical nature of Lrrk2 in the development of Parkinson's disease and lay the groundwork for the development of targeted therapeutics for the treatment of Parkinson's disease.